Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases but surprisingly no one has tried to see if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide hypocretin, also known as orexin. We have constructed a replication-defective herpes simplex virus-1 (HSV-1) amplicon-based vector to transfer the gene for mouse prepro-hypocretin into the brains of two reliable and established murine models of narcolepsy. We are focusing on transferring the gene for mouse prepro hypocretin because this neuropeptide can be easily identified using simple immunohistochemical procedures. Our very strong preliminary data shows abundant and robust expression of hypocretin in the lateral hypothalamus, release of the peptide into the CSF and unambiguous decline of narcoleptic symptoms in two murine models of narcolepsy. In this project an integrated series of aims will address the following questions: Which narcoleptic behavior in the mouse models is most sensitive to the gene transfer? Is it partial or complete reversal? Is the effect site specific? Are the neurons connected to pontine sites implicated in REM sleep? Experiments with appropriate controls are proposed to strengthen the conclusions. These studies will demonstrate that genetic pharmacology can be a neurobiological method that can be used to repair the network. PUBLIC HEALTH RELEVANCE: Narcolepsy is now considered a neurodegenerative disorder and it is necessary to explore new strategies to treat the disease. The significance of this project is that it will develop a gene transfer approach that will serve as a neurobiological tool to understand the networking underlying narcolepsy and also to ultimately restore some function.